Rapid Intravenous Injection Research Articles

Sudden Death Induced by Rapid Intravenous Injection of Fentanyl in Conscious Rats

The sudden death induced by rapid intravenous (IVr) injection of overdose FNT in clinical settings is commonly observed in conscious humans and more often in the males than females. Our previous study has shown that IVr injection of FNT induces a long-lasting apnea associated with bradycardia and hypotension in anesthetized rats (Zhuang et al. 2023 EB). This study aimed to determine whether a lethal dose of FNT could cause sudden death with the mortality being higher in male rats than female ones and whether the FNT-induced respiratory disorder, especially ventilatory arrest, but not cardiac arrest, was the trigger of the death. The rat previously instrumented with ECG electrodes and jugular vein cannulation was placed in a restraint tube that was connected to a plethysmograph chamber to record cardiorespiratory activities. We found that FNT at doses <2 mg/kg induced an immediate persistent apnea, lasting less than 1 min, associated with bradycardia. Following restoration of respiratory rhythm, the rats showed depressed VE and bradycardia for several hours and the cardiorespiratory variables recovered next day. A lethal dose of FNT at 3 mg/kg, compared to FNT at <2 mg/kg, induced an even longer apnea (lasting >1.5 min) accompanied with more severe bradycardia. This sustained apnea was usually interrupted by brief restoration of breathing, which was followed by ventilatory and cardiac arrest occurring at approximately 5 min and 10 min post injection respectively. Although the initial cardiorespiratory response to FNT appeared to be similar in both genders, the death rate was relatively higher in male rats than female ones. In conclusion, our study establishes an animal model of IVr injection of overdose FNT-induced sudden death occurring within minutes. The sudden death is the result of ventilatory, but not cardiac, arrest following a brief restoration of respiratory activity from a sustained apnea. Supported by NIH R01 grants HL163512 and DA059063. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Inhalation of Aerosolized Fentanyl Induces Respiratory Disorder and Sudden Death in Anesthetized Rats

In synthetic opioids, fentanyl (FNT) is the deadliest in clinical settings, resulting from respiratory disorder (RD) including ventilatory depression (dVE) and apnea. Rapid intravenous injection of FNT has been reported to cause immediately central and upper airway obstructive apnea that is mediated by vagal afferents in anesthetized rat (Zhuang J et al, 2012 and 2023). Here we asked whether acute inhalation of FNT also induced similar RD. EMGs of the internal and external intercostal muscles and thyroarytenoid muscles (EMGII, EMGEI, and EMGTA), minute ventilation (VE), heart rate and arterial blood pressure were recorded in anesthetized rats exposed to aerosolized FNT for 10 min. Immediately after exposure to FNT at 100 mg/m3, the rats showed apneas and remarkable prolongation of expiratory duration (TE) associated with hypotension and bradycardia. The apneas were characterized by cessation of EMGEI activity (central apnea) with enhanced tonic discharges of EMGTA (vocal closure, i.e., obstructive apnea) and EMGII (expiratory muscle constriction, i.e., chest wall rigidity). After a brief rebound at ~0.5 min exposure when the cardiorespiratory activities almost recovered to the baseline level, the rats presented gradual dVE by reduction of VT and fR, lasting for approximately 10 min. Apneas and ventilatory arrest subsequently occurred, leading to cardiac arrest a few minutes later. In contrast, FNT at 50 mg/m3 initially failed to significantly change VE, but subsequently developed gradual dVE (70% reduction) with significant TE prolongation, bradycardia and hypotension. These cardiorespiratory responses disappeared 30 min later. Our results suggest that acute exposure to a lethal dose of aerosolized FNT initially induces both central and upper airway obstructive apnea followed by dVE and ventilatory arrest, which is responsible for the sudden death in anesthetized rats. Supported by NIH R01 grants HL163512 and DA059063. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effect of Nonionic Iodinated Contrast Media on Blood Pressure during Contrast-enhanced Computed Tomography of Abdomen Examination: A Cross-sectional Study

ABSTRACT Introduction: Computed tomography (CT) scan has high sensitivity and specificity for numerous conditions. The images produced by a CT scanner can be enhanced using iodinated contrast media. Significant hemodynamic changes are seen with rapid intravenous contrast media injection. The average acceptable blood pressure (BP) value is 120/80 mmHg. Many studies have related hypertensive crises with high-osmolar contrast media, whereas its relation with low-osmolar contrast media is still unclear. This study aims to evaluate the effect of nonionic iodinated contrast media on BP during contrast-enhanced CT (CECT) of the abdomen. Materials and Methods: A cross-sectional study was conducted from April 2022 to August 2023. A total of 146 subjects (73 males and 73 females were included in the study). Statistical analysis of data was done using SPSS 23.0. A comparison of systolic BP and diastolic BP across the three periods was done using repeated measures of ANOVA. A between-group comparison was performed by unpaired t-test. The level of significance was set as 5%. All subjects underwent a CECT abdomen, including a plain, arterial, and venous phase. A bolus of 80 mL of Ultravist was administered. BP was measured before the contrast injection (baseline value), between the arterial and venous phases, and 3 min after the contrast injection. Results: Injection of nonionic contrast media caused a decrease in BP among subjects. The mean systolic BP readings before contrast injection in males and females were 127.5 ± 8 mmHg and 122.8 ± 8.4 mmHg, respectively. The mean diastolic BP before contrast injection was 79.2 ± 6.4 and 76 ± 6.4 mmHg among males and females, respectively. For systolic, these values decreased to 123 ± 10.3 mmHg in males and in females to 115 ± 14.6 mmHg when measured between arterial and venous phases. Similarly, for diastolic BP, the mean values recorded between the arterial-venous phase reduced to 76.7 ± 9.3 mmHg and 72.3 ± 10 mmHg, respectively. The BP readings, however, increased near baseline value when measured 3 min after the injection. The mean systolic BP measured 126.1 ± 8.5 mmHg and 124.9 ± 11.8 mmHg for males and females at 3 min after injection. Similarly, the mean diastolic BP values taken after 3 min of contrast injection were 78.3 ± 6.5 mmHg and 76.2 ± 7 mmHg in males and females, respectively, P < 0.001. BP in both male and female groups was affected similarly. Conclusion: Bolus administration of 80 mL of Ultravist reduced BP. This reduction was short-term and got back to normal within a few minutes. The contrast media similarly affected both genders. The BP changes had no clinical significance.

Examination of postmortem changes in the lungs, trachea, and bronchi in a rat model imaged with small-animal computed tomography.

As less autopsies are performed, the need for postmortem computed tomography (PMCT) as an alternative is increasing. It is important to know how postmortem changes over time are reflected on CT, in order to improve the diagnostic capability of PMCT and replace forensic pathology evaluations such as time of death estimation. In this study, we examined temporal changes on postmortem chest CT images of a rat model. After acquiring antemortem images under isoflurane inhalation anesthesia, the rats were euthanized with a rapid intravenous injection of anesthetics. From immediately after death to 48 hours postmortem, chest images were acquired using small-animal CT. The 3D images were then evaluated on a workstation to measure the antemortem and postmortem air content in the lungs, trachea, and bronchi over time. The air content in the lungs decreased, but the air content of the trachea and bronchi temporarily increased 1-12 hours postmortem, then decreased at 48 hours postmortem. Therefore, the measurement of trachea and bronchi volumes on PMCT could be an objective way to estimate the time of death. While the air content of the lungs decreased, the volume of the trachea and bronchi temporarily increased after death, indicating the potential to use such measurements to estimate time of death.

Recrystallization of Adenosine for Localized Drug Delivery.

Adenosine (ADO) is an endogenous metabolite with immense potential to be repurposed as an immunomodulatory therapeutic, as preclinical studies have demonstrated in models of epilepsy, acute respiratory distress syndrome, and traumatic brain injury, among others. The currently licensed products Adenocard and Adenoscan are formulated at 3 mg/mL of ADO for rapid bolus intravenous injection, but the systemic administration of the saline formulations for anti-inflammatory purposes is limited by the nucleoside's profound hemodynamic effects. Moreover, concentrations that can be attained in the airway or the brain through direct instillation or injection are limited by the volumes that can be accommodated in the anatomical space (<5 mL in humans) and the rapid elimination by enzymatic and transport mechanisms in the interstitium (half-life <5 s). As such, highly concentrated formulations of ADO are needed to attain pharmacologically relevant concentrations at sites of tissue injury. Herein, we report a previously uncharacterized crystalline form of ADO (rcADO) in which 6.7 mg/mL of the nucleoside is suspended in water. Importantly, the crystallinity is not diminished in a protein-rich environment, as evidenced by resuspending the crystals in albumin (15% w/v). To the best of our knowledge, this is the first report of crystalline ADO generated using a facile and organic solvent-free method aimed at localized drug delivery. The crystalline suspension may be suitable for developing ADO into injectable formulations for attaining high concentrations of the endogenous nucleoside in inflammatory locales.

The superior laryngeal nerve is involved in a brief apneic response to intralaryngeal, but not in the lethal ventilatory arrest to intravenous, administration of fentanyl (FNT) in rats

Rapid intravenous (IV) injection of FNT induces a sudden ventilatory arrest within a few minutes or even seconds, which is the major cause of overdose FNT‐induced death. Our previous studies have shown that right atrial or IV bolus injection of FNT in anesthetized rats produced a vagal‐mediated apnea or a lethal ventilatory arrest in a dose‐dependent manner (Zhuang et al, AJP 2012 and EB Meeting 2022). The superior laryngeal nerve (SLN) containing the laryngeal sensory afferents also travels in the vagus nerve and is capable of triggering the apneic response associated with hypertension and bradycardia upon activation. Here, we asked whether local administration of FNT into the larynx affected cardiorespiratory activities via acting on the SLN and to what extent the sudden ventilatory arrest induced by IV injection of FNT depended on the SLN integrity. FNT at 15 µg was either sprayed (5‐10 µl) into the larynx or bolus IV‐injected (50 µl) in the anesthetized rats with and without bilateral SLN transection. We found that FNT sprayed into the larynx induced an immediate brief apnea (~3.5‐fold of baseline TE) and laryngeal constriction (but not closure) associated with hypertension and bradycardia. The cardiorespiratory response disappeared after transection of SLN. Interestingly, the same dose of FNT given by IV injection induced a ventilatory arrest (apneic duration &gt;8‐fold longer than that produced by the local administration) associated with laryngeal closure, hypotension and bradycardia. These responses to IV injection of FNT were not significantly affected by SLN transection. Our data suggest that the SLN is responsible for the brief apneic response to laryngeal application of FNT, but not for the lethal ventilatory arrest induced by rapid IV injection of FNT.

Rapid Intravenous Injection of Fentanyl (FNT) Causes a Vagal‐Mediated Lethal Sudden Ventilatory Arrest in Anesthetized Rats

Opioids have been used for analgesia and anesthesia mainly via activation of central opioid mu‐receptors (MORs). It also causes overdose deaths due to ventilatory failure, in which FNT is the deadest. Rapid intravenous (IV) injection of overdose FNT triggers a sudden death within a few minutes or even seconds, but the relevant mechanism remains unclear. Because bolus IV injection of FNT at a low dose produced a vagal‐mediated brief apnea (Zhuang et al, AJP 2012), This study was aimed to characterize the cardiorespiratory disorders responsible for the sudden death and determine the vagal role in generating the lethal ventilatory arrest. EMGs of external and internal intercostal (EMGEI and EMGII), thyroarytenoid and superior pharyngeal constrictor muscles (EMGTA and EMGSPC) were simultaneously recorded before and after IV injection of FNT in the anesthetized vagal intact and vagotomized rats. The optical fiber scope of an oral video camera was applied to visualize the vocal and pharyngeal responses. Immunohistochemical approach was used to define the presence of MOR expression in the pulmonary vagal sensory neurons retrogradely labeled by DiI. FNT induced an apnea or a lethal ventilatory arrest in a dose‐dependent manner associated with hypotension and bradycardia. The apnea/ventilatory arrest was characterized by silence of EMGEI with tonic discharges of EMGII, EMGTA, and EMGSPC, i.e., the central apnea (expiratory) coupled with vocal closure and pharyngeal constriction/collapse and chest wall rigidity (triple‐apnea). Vagotomy abolished the evoked cardiorespiratory responses. MOR expression in vagal pulmonary neurons, especially C‐neurons of the nodose and jugular ganglia. Our results suggest that rapid IV injection of FNT at a high dose uniquely causes a vagal‐mediated triple‐apnea, leading to the sudden death in anesthetized rats.

Comparison of Outcomes in Patients with Obesity Between Two Administration Routes of Omeprazole After Laparoscopic Sleeve Gastrectomy: An Open-Label Randomized Clinical Trial

BackgroundThe effect of different administration routes of omeprazole remains unclear on the recovery in patients with obesity after laparoscopic sleeve gastrectomy (LSG).MethodsWe designed a randomized clinical trial enrolling 120 patients with a BMI≥32.5 kg/m2 after LSG. They were randomized into two groups to be administered with omeprazole by rapid intravenous injection (group A) or by continuous micropump infusion (group B). The plasma concentration of omeprazole was monitored upon initiating administration. Change in intragastric pH and gastrointestinal symptoms during follow-up served as indicators for therapeutic evaluation.ResultsPatients in the two groups showed no difference in the AUC curves (P=0.25), but group A had significantly higher peak concentration (P<0.001), and shorter time to reach peak concentration after administration (P<0.001), compared to group B. Before and after the administration of omeprazole, the average change in intragastric pH was much lower in group A (0.031 ± 0.61) than in group B (0.48 ± 0.74) (P=0.004). The incidence of gastrointestinal symptoms was similar between the two groups (P=0.85); however, the average duration of remaining symptoms was longer in group A (3.97 months; 95% CI, 2.90–5.04) than in group B (2.82 months; 95% CI, 2.01–3.63) (P=0.04).ConclusionContinuous micropump infusion of omeprazole may improve the outcomes in patients with obesity after LSG.Trial registrationChina Clinical Trial Registration Center (ChiCTR), ChiCTR-IPR-17013365. Registered 13 November 2017. http://www.chictr.org.cn/showproj.aspx?proj=22892.

The Efficacy of Combined Medication With Methylprednisolone and Erythropoietin in the Treatment of Ischemia-Reperfusion Injury to the Spinal Cord in Patients With Cervical Spondylotic Myelopathy.

IntroductionCervical myelopathy (CM) is caused by degenerative or congenital changes in the discs and soft tissues of the cervical spine, leading to chronic compression of the spinal cord. The current treatment for moderate-to-severe CM is surgical decompression, which is effective in most cases; however, it can cause inflammation of the nervous system and spinal cord reperfusion injury, resulting in perioperative neurological complications and suboptimal neurological recovery. The aim of this study was to investigate the therapeutic effects of the combination of erythropoietin and methylprednisolone in the treatment of ischemia-reperfusion injury to the spinal cord and to analyze its effects on the levels of interleukin-1 beta (IL-1β), interleukin-1 receptor antagonist (IL-1RA), and interleukin-8 (IL-8).Materials and methodsThis study included 110 patients admitted to the hospital due to cervical spondylotic myelopathy. They were randomized into two groups of 55 patients each: a control and an observation group. In both groups of patients, fusion internal fixation and anterior cervical discectomy were performed. The difference, however, was that the control group received a rapid intravenous injection of 30 mg/kg methylprednisolone 30 minutes prior to spinal cord decompression, while the observation group received an intravenous injection of 30 mg/kg methylprednisolone and 3,000 U/kg erythropoietin 30 minutes before spinal cord decompression. The study was approved by the Hospital Ethical Committee of the Dow University of Health Sciences, Karachi. The neurological function of both groups of patients was assessed before the procedure and three months after the treatment using the Japanese Orthopedic Association (JOA) method of assessing spinal cord function (40-point rating method). Enzyme-linked immunosorbent assay (ELISA) was performed to measure the levels of neuron-specific enolase (NSE), S-100β, IL-1RA, IL-1β, and IL-8 in both groups. The quality of life of patients in both groups was assessed three months after the treatment with the World Health Organization Quality of Life assessment instrument (WHOQOL-100).ResultsBefore the treatment, there was no significant variance between the two groups in the JOA score and the 40-point rating method. Similarly, there was no significant difference in the levels of IL-1β, IL-1RA, and IL-8 between the two groups (p-value = 0.262, 0.387, and 0.154 respectively) prior to the treatment. Three months after the treatment, the levels of IL-1β and IL-8 in the observation group were 21.83 ±3.65 ng/l and 357.07 ±32.36 ng/l respectively, both lower than the control group value (p-value = 0.026, 0.028 respectively). The level of IL-1RA in follow-up was 21.59 ±1.15 ng/l, which was higher than that in the control group. Three months after the treatment, all the WHOQOL-100 parameters of the observation group for psychology, physiology, social relations, independence, spirituality, environment, and general quality of life were higher than those of the control group; the variance among the groups was statistically significant (p-value: <0.001).ConclusionsThe combination therapy with erythropoietin and methylprednisolone is effective for ischemia-reperfusion injuries of the spinal cord. It also reduces S-100β and NSE, inhibits IL-1β, and increases IL-8 and IL-1RA. Therefore, it preserves and improves spinal nerve function and the quality of life of patients.

Imaging primer for CT angiography in peripheral vascular trauma.

The use of computed tomography angiography (CTA) for the evaluation of peripheral vascular trauma has become increasingly prevalent in the past decade with the development of multidetector CT (MDCT) and multiple studies subsequently demonstrating high sensitivity, specificity, and diagnostic accuracy when compared with conventional angiography. Additional benefits of MDCT include the ability to rapidly acquire the images, perform multiplanar and 3D reconstructions, and assess the adjacent soft tissues and bones. Rapid intravenous injection of iodinated contrast material is required for optimal arterial enhancement. CTA manifestations of an arterial injury may be direct, and include active contrast extravasation, pseudoaneurysm, arteriovenous fistula (AVF), intimal injury, dissection, or occlusion. There are also indirect signs which have a high association with vascular injury, and should raise suspicion, when present. Pitfalls related to image acquisition or patient factors can be mitigated with appropriate planning and post-processing techniques.

Constant-rate intravenous infusion of indocyanine green leading to high fluorescence intensity in infrared thoracoscopic segmentectomy.

ObjectivesThe purpose of this study was to determine whether or not fluorescence could be increased by administering indocyanine green at a constant rate, thus stabilizing its blood concentration.MethodsIn 20 consecutive patients undergoing segmentectomy, the dominant pulmonary arteries were ligated, blocking blood in the target segment. Fluorescence intensity was then observed using different indocyanine green administration methods under infrared thoracoscopy. Intravenous administration of indocyanine green, via a syringe pump at a rate of 12.5 mg/min, was defined as the constant rate group. The bolus group was defined by a 5-mg indocyanine green rapid intravenous injection. The fluorescence intensity was compared at the time of maximum fluorescence and 2 minutes after fluorescence initiation.ResultsAt maximum staining, the fluorescence intensity of the normal blood flow area was brighter in the constant rate group (median, 184.2; interquartile range, 170.2-200.1) compared with the bolus group (median, 122.3; interquartile range, 87.3-144.7; P = .0003). The fluorescence of the normal blood flow was retained even after 2 minutes. There was no difference in the fluorescence intensity of the ischemic segments.ConclusionsThe constant rate method showed brighter and better fluorescence than the bolus injection, without an increase in the dose. The contrast between adjacent segments was clear, facilitating the differentiation of the areas.

Effect of bolus administration of non-ionic radiopaque contrast media on blood pressure variation

IntroductionHaemodynamic changes may occur with the rapid intravenous injection of contrast media due to the osmolality of such pharmaceuticals. This study sought to evaluate the effect of bolus administration of intravenous contrast media on blood pressure variation during the Contrast-Enhanced Computed Tomography (CECT) of the abdomen. MethodsThe study included 74 patients who underwent abdominal CECT and they were placed in the first group receiving a maximum of 80 ml of iodinated contrast via pressure injector (4 ml/s). A further 74 patients, who underwent non-contrast enhanced abdominal CT, were placed in the second group in which 80 ml of normal saline was administered via the same manner. Patients with hypertension and who were on anti-hypertensive drugs were excluded from the study. Non-invasive blood pressure was monitored before the injection of contrast media/saline and immediately after the portal venous phase for the CECT scan and after 45 s following the administration of normal saline in the non-contrast CT group. Mean systolic and diastolic blood pressures from both groups were compared to find out the effect of contrast bolus administration on blood pressure variation. ResultsBoth systolic and diastolic blood pressure increased with the injection of contrast media among CECT scan group. No significant changes in systolic and diastolic blood pressure were found before and after the scan in the non-contrast group. ConclusionBolus administration of 80 ml saline has no effect on blood pressure. The increased blood pressure in contrast enhanced studies was induced by the iodinated contrast media and not by the bolus effect.

Intermittent intake of rapid cocaine injections promotes the risk of relapse and increases mesocorticolimbic BDNF levels during abstinence.

Cocaine is thought to be more addictive when it reaches the brain rapidly. We predicted that variation in the speed of cocaine delivery influences the likelihood of addiction in part by determining the risk of relapse after abstinence. Under an intermittent-access schedule, rats pressed a lever for rapid (injected over 5 s) or slower (90 s) intravenous cocaine injections (0.5 mg/kg/injection). Control rats self-administered food pellets. A tone-light cue accompanied each self-administered reward. The 5s- and 90s-rats took a similar average amount of cocaine. Oneor 45 days after withdrawalfrom cocaine/forced abstinence, lever-pressing behaviour was extinguished during a 6-h session. Immediately thereafter, cue- or cocaine (10 mg/kg, i.p.)-induced reinstatement was assessed for 1 h. Oneor 45 days after withdrawal, only 5s-rats showed significant cocaine-induced reinstatement of reward-seeking behaviour. Inboth cocaine groups, cue-induced reinstatement behaviourwas more pronounced after 45daysthan after 1day of withdrawal from cocaine, indicating incubation of conditioned drug craving. However, cue-induced reinstatement after extended abstinence was greatest in the 5s-rats. Brain-derived neurotrophic factor (BDNF) activity in the brain regulates reinstatement behaviour. Thus, 24 h after reinstatement tests, we measured BDNF protein concentrations in mesocorticolimbic regions. Only 5s-rats showed time-dependent increases in BDNF concentrations in the prelimbic cortex, nucleus accumbens core and ventral tegmental area after withdrawalfrom cocaine (day 45 > day 1). Thus, rapidly rising brain cocaine levels might facilitate addiction by evoking changes in the brain that intensify drug craving after abstinence, and these changes persist long after the last bout of cocaine use.

EVALUATION OF BLOOD PRESSURE VARIATIONS DURING THE ADMINISTRATION OF INTRAVASCULAR CONTRAST MEDIA IN CECT ABDOMEN

Objective: Hemodynamic changes may occur with the rapid intravenous injection of contrast media due to the osmolality of contrast media. This study is aimed to evaluate the blood pressure variation during the administration of intravascular contrast media in contrast-enhanced computed tomography (CECT) of the abdomen.Methods: The study was performed in 146 subjects, who underwent abdomen CT scan with 64-slice Philips Brilliance CT scanner in the department of radio-diagnosis and imaging. Using convenience sampling technique, 73 subjects who were referred for CECT abdomen scan and another 73 subjects who were referred for non-CECT (NCECT) abdomen scan were included in the study. Among the CECT group, intravascular contrast media was injected into the patient during the scan. Both systolic and diastolic blood pressures were recorded just before and immediately after the scan in CECT and NCECT groups, by two readers independently. Mean systolic and diastolic blood pressure for both groups was calculated with standard deviation. The data were analyzed using repeated measures of ANOVA.Results: Both systolic and diastolic blood pressures increased with the injection of contrast media among CECT scan group. No significant changes in systolic and diastolic blood pressure were found before and after the scan of NCECT group.Conclusion: An increase in both systolic and diastolic blood pressures is associated with the intravascular administration of non-ionic low-osmolar contrast media.

Early postmortem biochemical and histopathological changes in the kidney, liver, and muscles of dogs

The goal of the present study was to investigate the biochemical and histological changes in dog’s kidney, liver, heart, and skeletal muscles within 72 h after death. Ten male mongrel dogs aged from 1 to 2 years old were subjected to this study. Dogs were euthanized by the rapid intravenous injection of a lethal dose of sodium thiopental, and then the liver, kidney, heart, and skeletal muscle samples were collected from the whole carcasses at different time intervals 4, 12, 24, 48, and 72 h postmortem. Samples were divided into two parts; one part was used for measuring tissue levels of lactate dehydrogenase (LDH), lactate, creatine phosphokinase (CPK), and aspartate aminotransferase (AST). The other part was subjected to histopathological examinations. On the biochemical level, LDH in the liver, kidney, and cardiac and skeletal muscles showed a significant increase at 4 h followed by significant decrease at 48 and 72 h in all the studied tissues. Lactate level showed variable degrees of increase and decrease in kidney and liver tissues while muscles showed increased lactate concentration during the first 48 h then decreased at 72 h. CPK in cardiac and skeletal muscles showed similar changes; it increased from 4 to 48 h then decreased at 72 h. AST level decreased in liver tissue at 4 until 72 h, while in muscular tissue it showed a delayed reduction in concentration which started at 12 and 24 h in the cardiac and skeletal muscles respectively. Similar changes of AST levels in both skeletal and cardiac muscles were observed; it increased at 4 h and then decreased at 24, 48, and 72 h. Histopathological changes in the kidneys were the earliest changes seen in tissue. The changes in the hepatic tissue were earlier than those of heart and skeletal muscle. We concluded that LDH enzyme showed regular changes in all examined tissues; the biochemical changes in cardiac and skeletal muscles were regular and can be useful in estimation of the time of death. The histopathological changes in the kidney, liver, and cardiac and skeletal muscles were very clear and can be used for estimating the postmortem intervals in dogs.

Induction of Nephrotic Syndrome in Mice by Retrobulbar Injection of Doxorubicin and Prevention of Volume Retention by Sustained Release Aprotinin.

Nephrotic syndrome is the most extreme manifestation of proteinuric kidney disease and characterized by heavy proteinuria, hypoalbuminemia, and edema due to sodium retention and hyperlipidemia. To study the pathophysiology of this syndrome, rodent models have been developed based on the injection of toxic substances such as doxorubicin causing podocyte damage. In mice, only few strains are susceptible to this model. In wildtype 129S1/SvImJ mice, the administration of doxorubicin by rapid intravenous injection to the retrobulbar sinus induces experimental nephrotic syndrome that features all the symptoms of human disease including sodium retention and edema. After the onset of proteinuria, mice exhibit increased urinary serine protease activity that leads to the activation of the epithelial sodium channel (ENaC) and sodium retention. Pharmacological inhibition of urinary serine proteases by the treatment with sustained release aprotinin abrogates ENaC activation and prevents sodium retention. This model is ideal to study the pathophysiology of proteasuria, i.e., the excretion of active serine proteases that cause ENaC activation by the proteolysis of its γ-subunit. This can be regarded as the primary mechanism of ENaC activation and sodium retention in proteinuric kidney disease.

Pharmacokinetics of Snake Venom.

Understanding snake venom pharmacokinetics is essential for developing risk assessment strategies and determining the optimal dose and timing of antivenom required to bind all venom in snakebite patients. This review aims to explore the current knowledge of snake venom pharmacokinetics in animals and humans. Literature searches were conducted using EMBASE (1974–present) and Medline (1946–present). For animals, 12 out of 520 initially identified studies met the inclusion criteria. In general, the disposition of snake venom was described by a two-compartment model consisting of a rapid distribution phase and a slow elimination phase, with half-lives of 5 to 48 min and 0.8 to 28 h, respectively, following rapid intravenous injection of the venoms or toxins. When the venoms or toxins were administered intramuscularly or subcutaneously, an initial absorption phase and slow elimination phase were observed. The bioavailability of venoms or toxins ranged from 4 to 81.5% following intramuscular administration and 60% following subcutaneous administration. The volume of distribution and the clearance varied between snake species. For humans, 24 out of 666 initially identified publications contained sufficient information and timed venom concentrations in the absence of antivenom therapy for data extraction. The data were extracted and modelled in NONMEM. A one-compartment model provided the best fit, with an elimination half-life of 9.71 ± 1.29 h. It is intended that the quantitative information provided in this review will provide a useful basis for future studies that address the pharmacokinetics of snakebite in humans.

Hemodynamic Effects of Lipid-Based Oxygen Microbubbles via Rapid Intravenous Injection in Rodents.

Low oxygen levels, or hypoxemia, is a common cause of morbidity and mortality in critically ill patients. Hypoxemia is typically addressed by increasing the fraction of inspired oxygen, the use of mechanical ventilation, or more invasive measures. Recently, the injection of oxygen gas directly into the bloodstream by packaging it within lipid-based oxygen microbubbles (LOMs) has been explored. The purpose of this work is to examine the acute hemodynamic effects of intravenous injections of LOMs. LOMs composed of 1,2-distearoyl-sn-glycero-3-phosphocoline and cholesterol were manufactured using a process of shear homogenization under an oxygen headspace. A 5mL aliquot of either PlasmaLyte A, or low (37%) or high (55%) concentration LOMs (n=10 per group) was injected over a 1min period into Sprague Dawley rats instrumented for measurement of cardiac index and pulmonary (PVR) and systemic (SVR) vascular resistance during a 60min observation period. Hemodynamics were compared between groups by linear mixed modeling. Approximately 1011 LOMs with mean diameter 3.77±1.19μm were injected over the 1min period. Relative to controls, rodents treated with high concentration LOMs exhibited a higher pulmonary artery pressure (20±0.4mmHg vs 18±0.4mmHg, P<0.001) and higher PVR (0.31±0.01 vs 0.23±0.01mmHg/mL*min*kg, P<0.001. Despite a stable cardiac index (62.2±3.5 vs 62.3±3.4mL/min*kg, P<0.001), mean arterial blood pressure decreased significantly in LOM-treated animals (46±2 vs 60±2mmHg, P<0.001) due to a decrease in SVR. Injections with aged LOM emulsions (>48h since manufacture) resulted in a higher incidence of hemodynamic collapse during the observation period (P=0.02). LOMs may be injected in quantities sufficient to deliver clinically meaningful volumes of oxygen but cause significant decrements in blood pressure and elevations in PVR.

Aberrant Left Subclavian Artery in a Beagle Puppy With a Persistent Right Aortic Arch. Use of Cone Beam Computed Tomography to Diagnose a Vascular Ring Anomaly

A 7-week-old, 1.045kg female beagle dog was referred to investigate a supposed vascular ring anomaly. Cone beam computed tomography with contrast enhanced arterial phase accomplished by a rapid manual intravenous injection of iodinated agent during the scanning process revealed a persistent right aortic arch and an aberrant left subclavian artery that compressed dorsally the esophagus in the cranial mediastinum. Third left intercostal thoracotomy was performed to transect the left subclavian artery. This is the first description of a vascular ring anomaly that was diagnosed with a cone beam computed tomography in veterinary medicine.

The influence of growth and E. coli endotoxaemia on amoxicillin pharmacokinetics in turkeys

ABSTRACT1. This experiment aimed to determine if the pharmacokinetics of amoxicillin (AMO) was affected by rapid growth or intravenous (i.v.) injection of Escherichia coli lipopolysaccharide (LPS).2. Turkeys of 2.0, 5.5 and 12.0 kg were administered i.v. or orally with AMO sodium at the dose of 15 mg/kg. Another group (5.7 kg) was treated with LPS prior to i.v. AMO administration. Plasma drug concentrations were determined using high-performance liquid chromatography and pharmacokinetic parameters were calculated using a non-compartmental model. To assess the haemodynamic effects of endotoxaemia, turkeys were subjected to echocardiography.3. During growth from 2.0 to 5.5 kg, the area under the drug concentration-time curve after i.v. AMO administration increased from 9.37 ± 2.43 to 21.29 ± 5.49 mg×h/ml. Total body clearance decreased from 1.72 ± 0.55 to 0.75 ± 0.12 l/h/kg. Growth to 12.0 kg did not further affect these parameters. Mean residence time and elimination half-life gradually increased. Pharmacokinetics of orally administered drug followed a similar pattern. LPS injection affected stroke volume, heart rate and resistance index. However, it did not affect the pharmacokinetic profile of AMO in survivors.4. It is concluded that rapid growth in turkeys affects AMO pharmacokinetics. Endotoxaemia, on the other hand, does not affect AMO elimination if compensatory mechanisms develop.